A Role for Voltage-Operated Calcium Channels in the Development of Oligodendrocytes

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Abstract

To determine whether L-type voltage-operated Ca ++ channels ( L-VOCCs ) are required for oligodendrocyte progenitor cell ( OPC ) development, we generated an inducible conditional knockout mouse in which the L-VOCC isoform Cav1.2 was postnatally deleted in NG2 positive OPCs. A significant hypomyelination was found in the brains of the Cav1.2 conditional knockout ( Cav1.2 KO ) mice specifically when the Cav1.2 deletion was induced in OPCs during the first two postnatal weeks. A decrease in myelin protein expression was visible in several brain structures including the corpus callosum, cortex and striatum, and the corpus callosum of Cav1.2 KO animals presented an important decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons. The reduced myelination was accompanied by an important decline in the number of myelinating oligodendrocytes and in the rate of OPC migration and proliferation. These results indicate that the L-VOCC isoform Cav1.2 modulates oligodendrocyte development, and suggest that Ca ++ influx mediated by L-VOCCs in oligodendroglial progenitor cells is necessary for normal myelination. To further investigate the role of L-VOCCs in the remyelination of the adult brain we used the cuprizone model of myelin injury and repair. We establish that Cav1.2 deletion in OPCs leads to less efficient remyelination of the adult brain. We have found that Cav1.2 deficient OPCs are less effective in remyelinating several structures of the adult brain including the corpus callosum and cortex. Specifically, Cav1.2 KO OPCs mature slower and produce less myelin than control oligodendrocytes after two and four weeks of recovery following the cuprizone intoxication. Furthermore, during the recovery period of the cuprizone model the corpus callosum of Cav1.2 KO animals presented an important decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compared to controls. These results suggest that Ca ++ influx mediated by L-VOCCs in oligodendroglial progenitor cells is necessary for normal remyelination and is an essential Ca ++ channel for OPC maturation during the remyelination process.